It is estimated that by 2020, over 450,000 Californians will suffer from vision loss or blindness due to the age-related macular degeneration (AMD), the most common cause of retinal degeneration in the elderly. AMD is a progressive ocular disease of the part of the retina, called the macula, which enables people to read, visualize faces, and drive. The disease initially causes distortion in central vision, and eventually leads to legal blindness. A layer of cells at the back of the eye called the retinal pigment epithelium (RPE), provides support, protection, and nutrition to the light sensitive cells of the retina; the photoreceptors. The dysfunction and/or loss of these RPE cells is believed to play a critical role in the subsequent death of photoreceptors and resulting loss of vision in AMD. Hence, if RPE cells can be restored, it may be possible to prevent or delay progressive vision loss in patients with AMD.
We are developing a therapy to replace RPE cells in patients with a form of AMD known as geographic atrophy. The RPE cells are delivered on a synthetic membrane, just as normal RPE cells in the eye are arranged as a thin layer of cells on a substrate known as the Bruch’s membrane. We have made excellent progress in the current grant period funded by CIRM and are on track to file to an investigational new drug application to the FDA to start the phase 1 human study. We have also shown that our approach of delivering the RPE as a sheet into diseased animal eyes has a much better chance of restoring retinal function than if these cells were injected as a suspension. In this current grant from CIRM, we are seeking to translate this preclinical work and to test this product in a Phase I clinical trial in patients with geographic atrophy.

Statement of Benefit to California:

Age-related macular degeneration (AMD) is the leading cause of vision loss and blindness among the elderly. It is estimated that over 1.75 million individuals in the US suffer from advanced AMD, and that this number will grow to nearly 3 million by 2020. Based on the demographics of California and the incidence rates of AMD among various age groups, it is anticipated that more than 400,000 Californians will develop advanced forms of AMD over the next 15 years. Although VEGF inhibitors such as Lucentis and Eylea provide therapeutic options for the wet form of AMD, no approved therapies currently exist for the advanced form of dry AMD, geographic atrophy, which is estimated to affect more than 100,000 Californians today, with another 160,000 new cases in California expected in the next 15 years. Studies have shown that the devastating consequences of AMD include the progressive loss of independence and productivity, and increased risks of falls, fractures, and depression among patients, resulting in substantial quality of life and economic impacts to many Californians. One health economics analysis estimated the total GDP from dry AMD in the United States to be more than $24 billion annually. Given that California accounts for more than 12% of US GDP, this analysis can be extrapolated to estimate that total GDP loss due to dry AMD in California is likely nearly $3 billion annually.
In the proposed project, phase I clinical testing of an implant composed of an ultrathin membrane coated with human embryonic stem cell-derived retinal pigment epithelial cells (RPE), one of the key cell types known to primarily degenerate or die in AMD, will begin in patients with advanced AMD. This project has been developed in California and clinical testing will begin in California. This project will benefit the state of California by providing treatment options for the hundreds of thousands of Californians with dry AMD, providing support for the further development of a therapy originally developed with California, and creating jobs in California by enabling the formation a new California-based start-up to further develop this product.

Review Summary:

EXECUTIVE SUMMARY
The goal of this proposal is to develop a cell therapy for the treatment of geographic atrophy, the advanced form of age-related macular degeneration (AMD), using human embryonic stem cell (hESC)-derived retinal pigment epithelium (RPE) cells. RPE cells form a layer at the back of the eye which provides support to the photoreceptor cells, the light-sensing cells of the eye. The RPE cells are delivered as a monolayer on a synthetic membrane, thereby mimicking the normal arrangement of RPE cells in the eye, where the cells are arrayed on a membrane known as the Bruch’s membrane. The proposal is a continuation of an ongoing Disease Team I project focused on the filing of an Investigational New Drug (IND) application for the candidate cell therapy. The key objective of this proposal is to translate the preclinical work completed under the previous Disease Team award by conducting a Phase 1 clinical trial in patients with geographic atrophy. An additional objective is to carry out manufacturing process improvements to optimize manufacturing of the cell therapy for future trials.
Significance and Impact
- This proposal is highly competitive with significant potential impact. There is a large unmet clinical need, and the use of RPE on an appropriately engineered substrate renders this a unique approach, distinct from approaches being employed in other trials.
- The proposed product could potentially prevent vision deterioration in patients with AMD and would be a big step forward from current treatments.
- Because both the RPE and the Bruch’s membrane are defective in AMD, this product has the potential to provide clinical benefit in this disease.
- The Target Product Profile (TPP) is well done and includes appropriate product attributes and metrics to enable decision making, and clearly defines optimal and minimally acceptable attributes of the final product.
Scientific Rationale and Risk/Benefit
- Strong scientific rationale is provided for implantation of RPE cells in retinal disease, supported by in vivo preclinical data.
- Considering the anatomy of the eye, the use of RPE cells appropriately oriented on a synthetic membrane may be superior to injection of cell suspensions in this disease. This approach should enhance the chance for success in patients with late stage disease where the Bruch's membrane is very abnormal.
- The risk/benefit ratio is appropriate given the design of the Phase 1 trial.
Therapeutic Development Readiness
- Preclinical proof of concept studies have been conducted and the investigators have evidence of safety and efficacy in preclinical models.
-No toxicity data are provided on the membrane alone.
- There was very little detail provided about an experimental surgical device that will be required to perform the transplantation procedure.
Design and Feasibility
- This is a very well conceived proposal. The preclinical plan, regulatory path, manufacturing strategy, and design of the study are all feasible and strong.
- Milestones capture the key activities for progress and the project timeline appears realistic and achievable
- In general the Phase 1 trial design is strong and the proposed follow-up period is commendable; the study population appears to be appropriate.
- Discussions with the regulatory agency have provided a clear path forward regarding the preclinical plan to support the proposed clinical trial.
- A minor concern is the collaboration with the manufacturers. It will be important to align key specific manufacturing activities to be conducted by contractors/suppliers.
- One reviewer had a concern that the proposed transplantation procedure might have a deleterious effect on graft survival.
- There is a potential for failed product runs and there are no data on production consistency.
Principal Investigator (PI), Development Team and Leadership Plan
- This is a strong team and there are no concerns.
- The leadership team and track record of this group are outstanding.
-This is an experienced investigator and very experienced development team
Budget
- The budget seems appropriate.
- A large budget line item for "other costs" needs to be explained.
Collaborations, Assets, Resources and Environment
- There are no concerns regarding the collaborations, contract services, resources and environment.
- The applicant needs to have commitment from the various manufacturers that they will meet the proposed timeline.